Preparing an IND Application: CBER Breakout Session

Donald W. Fink, Jr., Ph.D.Division of Cellular and Gene Therapies

Office of Tissue and Advanced TherapiesCenter for Biologics Evaluation and Research

Food and Drug Administration

FDA Clinical Investigator Training CourseNovember 15, 2018

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Products Regulated by CBER

Whole BloodBlood Components

Blood Derivatives and Recombinant Analogues

Devices

OBRR

Somatic Cellular & Gene Therapies

/ Tissues

Therapeutic Vaccines

XenotransplantationOTAT

Devices

Allergenic ExtractsPREVENTATIVE/TherapeuticVaccines: Infectious Diseases

OVRR

Diagnostic Skin TestsProbiotics

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21 CFR 1271.3(d)- Articles consisting of / derived from human cells or tissues intended for implantation, transplantation, infusion, or transfer, into a human recipient regulated as human cells, tissues and cellular and tissue-based products (HCT/Ps)

HCT/Ps may be eligible for regulation as tissues solely under Section 361 of the PHS Act and 21CFR § 1271

Cellular Therapies: Applying Tissue Regulations – 21 CFR §1271

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ONLY when ALL FOUR of the following are met:

Minimally Manipulated: Relevant biologic characteristic(s) are not altered by processingHomologous Use Only: The HCT/P performs the same basic function or

functions in the recipient as in the donor.Production of the HCT/P does not involve combination of cells with

another article: (limited exceptions and on the condition that addition of the excepted article does not raise new clinical safety concerns).No systemic effect, not dependent upon the metabolic activity of living

cells for primary function: exceptions for (a) autologous use, (b) first- or second-degree blood relatives, or (c) reproductive use.

HCT/P Regulation Solely Under Section 361 and 21 CFR 1271

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Minimally manipulated?

Homologous use? (normal function)

Combined with drug or device?

Systemic effect or dependent on

metabolic activity of the cells?

Tissue

Is it a sterilizing, preserving, or storage agent with no new clinical safety

concerns?

Autologous use?OR

Allogeneic use in first or second degree

relative?OR

Reproductive use?EXCEPTION

(compliance with 21 CFR 1271regulations not required whencells/tissues removed from andreturned to the patient during thesame surgical procedure: 21 CFR1271.15[b])

No

Yes

Yes

No

No

No

Yes

Yes

Yes

Yes

No

No

351Biologic

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Key Elements of the IND Submission

Chemistry, Manufacturing,

Controls

Clinical ProtocolRachel Witten, MD

Pharmacology/Toxicology

Allen Wensky, Ph.D.

INDAPPLICATION

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21 CFR 312.20 Subpart B: IND Application

Form FDA 1571 21 CFR 312.23(a)(1)

Table of Contents 21 CFR 312.23(a)(2)

Introductory statement and general investigational plan

21 CFR 312.23(a)(3)

Investigator’s brochure 21 CFR 312.23(a)(5)

Protocols 21 CFR 312.23(a)(6)

Chemistry, manufacturing, and control data (including environmental assessment 21 CFR 312.23(a)(7)

Pharmacology and toxicology data 21 CFR 312.23(a)(8)

Previous human experience 21 CFR 312.23(a)(9)

Additional information 21 CFR 312.23(a)(10)

Biosimilar User Fee Cover Sheet Form FDA 3792

Clinical Trials Certification of Compliance Form FDA 3674

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Ability to consistently and reproducibly manufacture your investigational cellular product using:

Well-controlled manufacturing process that relies on practices and procedures executed according to standardized written procedures.

Qualification program for source materials, reagents, ingredients, excipients and components used throughout the manufacturing process.

In-process and final product release testing that demonstrates overall product quality and safety/sterility.

Information Provided in CMC Section Should Demonstrate……

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Harnessing the Manufacturing Process

Chemistry,Manufacturing,Controls

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Helpful Reference: Preparing CMC Section for Cell-based Product IND

Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigation-al New Drug Applications (April 2008)

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm092705.pdf

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I. PRODUCT MANUFACTURING/CHARACTERIZATION Components and Materials

Cells: Autologous or Allogeneic, cell source/type (stem/progenitor or functionally specialized), description of characteristic attributes

Reagents/Materials/Excipients: List of all used during manufacturing process, indicate whether clinical grade. Describe qualification program for acceptance

Manufacturing Procedures Provide an outline of the manufacturing process for the cellular product including

timing for specific steps and overall duration Describe facility where manufacturing takes place, list equipment used, provide

information about the qualifications of persons responsible for performing manufacturing

Indicate final formulation, unit dosage, total number of units produced per manufacturing run, and method of storage if product not given fresh

CMC Guidance: Information to Include in IND Submission

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II. PRODUCT RELEASE TESTING/RESULTS Microbiological Testing Sterility Testing (Bacterial/Fungal): Performed in accordance with requirements outlined in

21 CFR 610.12. Sterility test appropriate to material being tested, does not interfere or hinder the test.

Test must be validated to demonstrate capability to reliably and consistently detect presence of viable, contaminating microorganisms.

Mycoplasma: Performed when manufacturing process involves extended periods of cell culture. May use recommended culture based assay, or PCR / other alternative test method (demonstrate adequate sensitivity/specificity). Test sample composition important

Adventitious Agents For cells recovered from allogeneic, unrelated donors: perform donor eligibility determination

for communicable diseases Cell Banks (Master and Working): In vivo and in vitro test methods for viral adventitious

agents as appropriate

CMC Guidance: Information to Include in IND Submission (cont.)

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II. PRODUCT RELEASE TESTING/RESULTS (2) Identity: assay that is specific for the cellular product, able to uniquely

identify product from others that may be manufactured in the same facility

Purity: testing performed to demonstrate the final product is free from undesired extraneous materials introduced during the manufacturing process.

Residual Contaminants: Assays to detect the presence of residual substances including cytokines, growth factors, antibodies, magnetic beads and serum used during manufacturing process and purification.

Pyrogenicity/Endotoxin (manufacturing process impurities)

CMC Guidance: Information to Include in IND Submission (cont.)

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II. PRODUCT RELEASE TESTING/RESULTS (3) Potency: Tests for potency shall consist of either in vitro or in vivo tests, or both,

which have been specifically designed for each product so as to indicate its potency Potency is interpreted to mean the specific ability or capacity of the product, as

indicated by appropriate laboratory tests….to effect a given result.

Biological Activity is… “the specific ability or capacity of a product to achieve a defined biological effect.” A measure of potency.

Potency assay(s) provides quantitative measurement of a relevant biological activity identified on the basis of preclinical testing and product characterization that is indicative of a cellular product’s capacity to elicit a clinical effect.

CMC Guidance: Information to Include in IND Submission (cont.)

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III. FINAL PRODUCT RELEASE TESTING: ACCEPTANCE CRITERIA (Drug Substance = Drug Product)

Release testing is performed on the final formulated product for each lot manufactured (could be N = 1)

Specifications/acceptance criteria, test methods for safety (sterility), purity, identity, and potency described in the IND.

Results from final product release testing should be available prior to patient administration.

If finalized test results will not be available prior to product/lot release, should include in IND reporting notification process in event acceptance criteria are not met.

Perform pilot manufacturing runs that demonstrate ability to manufacture cellular product that meets release test specifications/acceptance criteria.

CMC Guidance: Information to Include in IND Submission (cont.)

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IV. FINAL PRODUCT STABILITY IND should include description of stability testing program

developed to demonstrate cellular product is sufficiently stable for use throughout the time period covered by a clinical study.

Stability test panel should include assays to monitor product sterility, identity, purity, quality, and potency. Test results should meet specifications established prospectively.

For each assay included in the stability test panel, you should provide a description of the test method, indicate sampling time points, and specify composition of the test article.

CMC Guidance: Information to Include in IND Submission (cont.)

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V. OTHER ISSUES Product Tracking/Segregation:

You should include in IND submission information about adequate system to identify product from time of collection until patient administration

Include description of procedures developed to ensure segregation from other products manufactured in the same facility, preventing inadvertent cross-contamination

Labeling: Describe labeling used throughout manufacturing process and provide sample of label

affixed to the final cellular product

Label for investigational product must contain the statement: “CAUTION: New Drug –Limited by Federal law to Investigational Use”

Additional labeling necessary if donor eligibility testing is incomplete or not performed (e.g. cells for autologous use)

CMC Guidance: Information to Include in IND Submission (cont.)

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V. OTHER ISSUES (2) Processing/Manufacturing at Multiple Sites:

When cell processing/manufacturing is performed at several participating clinical sites, you should include in your IND a description of the plan used for qualifying manufacturing performed at each site.

Shipping From Single Manufacturing Location to Multiple Clinical Sites.Your IND submission should include a summary of testing performed to qualify product shipping procedures.

Product Delivery DeviceIf you will be using a novel device for product administration, or standard syringes and needles not developed for injection of a cellular product, you need to supply information in your IND demonstrating biocompatibility and uniform delivery of viable cell dose.

CMC Guidance: Information to Include in IND Submission (cont.)

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V. OTHER ISSUES (3) Lot-to-Lot Comparability Relevant when the quantity of initial source material or output of a

single manufacturing run may be insufficient to generate the total number of doses necessary to complete a clinical study

Describe in your IND in vitro and/or in vivo preclinical testing that will be conducted to demonstrate product comparability for: Separate manufactured lots produced from the same starting material

OR……

Separate manufactured lots produced from different starting material

CMC Guidance: Information to Include in IND Submission (cont.)

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Stages of Product Development

BLAPhase IIIPhase IIPhase IPreclinicalBench Testing

SafetyPotency

Qualification & Validation studiesProduct characterization

Stage of product development serves to determine key review issues, with safety being a primary focus during all stages of development/clinical testing.

IND Submission

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CMC Issues Typically Resulting in Placing an IND Going on Clinical Hold

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Opportunities for FDA Interaction

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INTERACT(Informal)

Pre-IND Meeting

30-day Review ClockPost BLA Meeting

Safety Meetings

Post-Marketing

BLAReview

CLINICAL TRIALSPh 1 Ph 2 Ph 3

INDReview

Pre-ClinicalDevelopment

IND Review PhasePre-IND Phase Marketing Application Phase

Post-marketing Phase

Product development is an iterative process that may involve multiple FDA and sponsor interactions

End of Ph 1 Meeting

End of Ph 2 Meeting

Pre-BLAMeeting

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• INTERACT (Initial Targeted Engagement for Regulagory Advice on CBER Products): Informal, Non-Binding Discussion: Generally CMC and Preclinical Topics, No Minutes GeneratedWebsite: https://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm

• Pre-IND / Type B: –Formal Meeting, Minutes Generated, Non-Binding Recommendations Sponsors and CBER/FDA staff discuss product development activities prior to

submission of an Investigational New Drug application (IND): may touch on CMC, Preclinical and Clinical topics

Represents a key juncture in the regulatory process

Rule of Thumb: Generally grant one Type B / pre-IND meeting prior to the submission of an IND: Exceptions do occur when circumstances dictate. Follow-up communication/ interaction is not uncommon

Early Interaction with FDA

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Determined by the maturity of your cellular product development efforts

Should have developed standard procedures that allow for reproducible product manufacturing: adequate cellular product characterization

“Right Time” to Request a Pre-IND Meeting: CMC Perspective

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The CMC section of your IND submission should include sufficient information regarding product manufacturing, release testing and characterization to permit assessment of the potential risks to subjects posed by the proposed clinical studies

A summary of the information expected in the CMC section of an IND for an investigational cellular product may be found in available published guidance.

Early interaction with FDA is encouraged during development to facilitate preparation of the IND submission, especially for particularly innovative products.

Take-Home Messages

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Donald W. Fink, PhDDonald.Fink@fda.hhs.gov

Regulatory Questions:OTAT Main Line: 240-402-8190Email: OTATRPMS@fda.hhs.gov andLori.Tull@fda.hhs.gov

OCTGT/OTAT Learn Webinar Series: http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

CBER website: www.fda.gov/BiologicsBloodVaccines/default.htm Phone: 1-800-835-4709 or 240-402-8010 Consumer Affairs Branch: ocod@fda.hhs.gov Manufacturers Assistance and Technical Training Branch:

industry.biologics@fda.gov Follow us on Twitter: https://www.twitter.com/fdacber

FDA HeadquartersFederal Research Center at White Oak

10903 New Hampshire AvenueSilver Spring, MD 20993-0002

www.fda.gov

Contact Information

Putting Together Your IND Submission(CBER): Preclinical Considerations

Allen Wensky, Ph.D.Center for Biologics Evaluation and Research (CBER)

Office of Tissues and Advanced Therapies (OTAT)Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT)

Pharmacology/Toxicology Branch (PTB)allen.wensky@fda.hhs.gov

CLINICAL INVESTIGATOR TRAINING COURSE (CITC): SESSION 7: INDs AND IDEs FROM START TO FINISH November 15, 2018

28

Overview

• Preclinical Regulatory Review Principles

• Potential Pitfalls / Regulatory Issues

• Early Interactions

• Resources

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Product Lifecycle for Biologics: Focus on the Preclinical Phase

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IND submission

Clinical TrialsPreclinical Marketing Application Post-marketing

BLAPhase 3Phase 2Phase 1PreclinicalDevelopment Post marketing

BLA submission

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What Regulations Govern Preclinical Testing?

Pharmacology & Toxicology Studies“…adequate information about the pharmacological and toxicological

studies…on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations.”

IND Regulations [21 CFR 312.23 (a)(8) - Pharmacology and Toxicology]

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• Final Guidance

Current thinking of the Agency on this topic First comprehensive FDA guidance on preclinical

assessment of cell and gene therapy (CGT) Products

Explicitly incorporates 3 R’s: recommendations to reduce, refine, and replace animal use in a preclinical program

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Expectations from Preclinical Data

• To support a rationale for the first-in-human clinical trial– For cell and gene therapy products, the trial is usually conducted in the disease

population, not in healthy volunteers• To make recommendations regarding the proposed clinical trial

– Initial safe starting dose, dose-escalation scheme, dosing schedule, organ toxicity, eligibility criteria, clinical monitoring

• To meet regulatory requirements– 21 CFR 312.23 (a)(8)– 21 CFR 58 (Good Laboratory Practice (GLP) compliance)

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CBER Review: Product-Based

• No “one size fits all” regulatory approach• Data necessary to support development depends on the

characteristics of the product• Preclinical studies are designed to support use of a specific product

for a specific clinical indication.• Review approach is based on balancing risk and benefit.

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Sources of Data to Support an IND

• GLP-compliant toxicology studies conducted by a certified testing facility

• Well-controlled studies conducted in house

• Published data in peer-reviewed journals

• Cross-reference to similar products in previously submitted files to FDA

• Detailed clinical study reports from clinical trials

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Preclinical Expectations for Early Phase Clinical Trials

• Potential mechanism of action (e.g., targeted killing, anti-tumor, tolerance induction)

• Establish pharmacologically effective dose(s)

• Optimize route of administration (ROA) / dosing regimen

• Establish rationale for species / model selection

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Preclinical Expectations for Early Phase Clinical Trials

• Establish a dosing scheme

• Potential target tissue(s) of toxicity / activity

• Parameters to monitor clinically

• Eligible patient population

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Preclinical Study Design(s)

• Assess pharmacology / proof-of-concept (POC) / vector distribution / cell fate in relevant animal model(s) of disease / injury, as feasible

• Assess safety / toxicology (T) / vector distribution / cell fate in healthy animals

• Hybrid pharmacology-toxicology study design– POC + T + product fate – incorporate activity and safety endpoints in an animal

model of disease / injury – Local microenvironment and pathophysiology status of the model may impact

the safety / bioactivity of the product

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Considerations for Appropriate Animal Species / Model

• There is no ‘default’ to the use of nonhuman primates

• There is no ‘default’ to the use of both a rodent and a non-rodent species

• There is no ‘default’ to the use of multiple species

• Understand the limitations of the species / model(s) used

• Scientific justification should be provided for the animal species / model(s) used

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Opportunities for Interaction -Preclinical Development

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IND submission

INTERACTPre-INDMeeting

End of Ph 1 Meeting

End of Ph 2 Meeting

Pre-BLAMeeting

PDUFA VMeetings

Safety Meetings

Clinical TrialsPreclinical Marketing Application Post-marketing

BLAPhase 3Phase 2Phase 1PreclinicalDevelopment Post marketing

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Early Communication with OTAT: INTERACT*

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• INitial Targeted Engagement for Regulatory Advice on CBER producTs (previously known as pre-pre-IND interactions)

• Goal: To obtain early feedback on a product development program for a novel investigational agent

• Purpose– A mechanism for early communication with OTAT – Non-binding, informal scientific discussions with CBER/OTAT review disciplines– Initial targeted discussion of specific issues– Primary contact: INTERACT-CBER@fda.hhs.gov

*https://www.fda.gov/BiologicsBloodVaccines/ResourcesforYou/Industry/ucm611501.htm

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Pre-IND Meeting: Preclinical

• Preclinical – A comprehensive summary of all completed preclinical studies (in vitro and in

vivo studies, animal species/models, study designs, product manufacturing and formulation, resulting data and interpretation)

– Discussion of the planned preclinical program (e.g., animal species/models, product manufacturing and formulation, study designs, ‘Animal Rule’ issues, etc.)

www.fda.gov

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Do’s for INTERACT and Pre-IND Meetings [Preclinical Perspective]

• Do read and understand FDA/ICH Guidances, regulations, etc. before meeting with FDA

• Do include the preclinical development plan• Do specify similarities and differences between the preclinical and

clinical products • Do specify similarities and differences between the preclinical and

clinical delivery devices/procedures• Do include the design of your completed and proposed preclinical

studies • Do make the package reader-friendlywww.fda.gov

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Don’ts for INTERACT and Pre-IND Meetings [Preclinical Perspective]

• Don’t conduct the definitive preclinical studies without seeking input from CBER/OTAT

• Don’t forget to discuss the limitations for each test system used• Don’t forget to consider new in vitro and in vivo test models as

the science and technology progress• Don’t forget that the preclinical testing program may need to

be adapted to the specific cell therapy product and level of risk

www.fda.gov

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Summary

• It is important to keep FDA / CBER / OTAT involved at an early phase of the product development program

• The preclinical study designs should be supported by scientific rationale / data

• Novel therapies mean novel testing paradigms

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Selected Guidances

• Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November 2013)http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM329861.pdf

• Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products (June 2015)http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM359073.pdf

• Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines (October 2011) http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM278673.pdf

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Contact Information• Allen Wensky

allen.wensky@fda.hhs.gov

• Regulatory Questions:

OTAT Main Line – 240 402 8190

Email: OTATRPMS@fda.hhs.gov and

Nannette.Cagungun@fda.hhs.gov

• OTAT Learn Webinar Series:

http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

• CBER website: www.fda.gov/BiologicsBloodVaccines/default.htm

• Phone: 1-800-835-4709 or 240-402-8010

• Consumer Affairs Branch: ocod@fda.hhs.gov

• Manufacturers Assistance and Technical Training Branch: industry.biologics@fda.hhs.gov• Follow us on Twitter: https://www.twitter.com/fdacber

FDA Headquarters

www.fda.gov

Putting Together Your IND Application(CBER): Clinical Considerations

Rachel Witten, M.D.Center for Biologics Evaluation and Research (CBER)

Office of Tissues and Advanced Therapies (OTAT)Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT)

CLINICAL INVESTIGATOR TRAINING COURSE 2018 (CITC): SESSION 7: INDs AND IDEs FROM START TO FINISH November 15, 2018

48

Overview

www.fda.gov

What is an IND? When do you need an IND? Who can apply for an IND? What should an IND contain? How does FDA review an IND? Expectation for a First-in-Human Study

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Investigational New Drug application

• A formal document with defined structure and content• Purpose is to request exemption from premarketing requirements and

to allow lawful shipment of drug for clinical investigation

Regulations (21CFR312) outline requirements

• Use of Investigational drug• Submission of application to FDA• Review by FDA

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When Do You Need to Submit an IND Application

An IND application is required for:Clinical investigation of a new drug or biologicChange to an existing approved drug or biologic, including a new: Indication or significant labeling or advertising change Dosage form and schedule Route of administration Patient population (e.g., pediatric, gender)

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Exemptions From IND Application

Criteria for exemption from the IND regulations (21 CFR 312.2(b)) • Drug or biologic product is lawfully marketed in the United States• No intent to support new use or labeling change• No intent to support change in advertising• No new factor --- such as route of administration, dosage, or study

population --- that significantly increases risk• No promotion or representation of product as safe or effective treatment

for condition under study

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Who can apply for IND application

• IND applicant is called a “sponsor”Sponsor takes responsibility for and initiates a clinical investigation

• IND sponsor may be a company, institution, or an individual• IND sponsor-investigator

An individual who both initiates and conducts the clinical trial

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You Have Decided to Submit an IND Application

• The time required to prepare an IND will depend on available information on product characterization, extend of pre-clinical data, and any clinical data from relevant studies.

• Study the relevant FDA instructions and forms. • Determine how your organization can best meet those requirements.

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Pre-IND meetingHighly recommended for new products

• A consultation provided to sponsors and investigators planning to submit an IND application

• This meeting is usually scheduled 3-9 months before the planned IND submission

• Pre-IND package may include: IND product’s characteristics manufacturing processes planned or completed pre-clinical studies development plan design of the planned investigation in humans Please provide specific questions to the Agency about any or all of the above.

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Know IND Application’s Content and Format (21 CFR 312.23(a))

• Form 1571 (21 CFR.§312.23(a)(1))• Table of Contents (21 CFR.§312.23(a)(2))• Introductory Statement (21 CFR.§312.23(a)(3))• General Investigational Plan• Investigator’s Brochure (21 CFR.§312.23(a)(5))• Clinical Protocols 21 CFR.§312.23(a)(6))• Form 1572 (21 CFR.§312.23(a)(6))• Chemistry, Manufacturing & Control Information (21 CFR.§ 312.23(a)(7))• Pharmacology & Toxicology information (21 CFR.§312.23(a)(8))• A summary of previous human experience with the investigational product

(21 CFR.§312.23(a)(9))• Additional or relevant Information (e.g., reference to previous submissions)

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Structure of the FDA Review Team

• Regulatory project manager• CMC product reviewer• Preclinical pharm/tox reviewer• Clinical reviewer• Biostatistician• Consultants

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IND Application: Protocols 21 CFR 312.23(a)(6)

Phase 1 protocol may be less detailed• Provide all the critical details regarding assessments of safety, including # of

patients, dosing plan, safety exclusion criteria, toxicity stopping rules, plan for staggering of subjects, and procedures for safety assessments

Phase 2 and 3 protocols provide sufficient details • Objectives and purposes should be clearly stated • The protocol should contain details of the observations and measurements to

be made to fulfill the objectives of the trial • The protocol should provide a description of clinical procedures, lab tests, and

all measures to be taken to monitor the effects of the drug

DON’T forget sufficient descriptions of safety monitoring in your protocol, irrespective of phase of development.

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The Procedural Aspects

• Regulatory review and all interactions with an IND sponsor must occur within 30 days of the receipt date:

• Information Requests • Teleconferences • Additional data submissions • Protocol modifications • By Day 30, the FDA will notify the sponsor that the IND application

(studies)

May proceed, OR will be placed on “HOLD”

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Understand the Grounds for Imposition of Clinical Hold (21 CFR 312.42)

Phase 1 studies• Human subjects are exposed to an unreasonable and

significant risk of illness or injury • Clinical investigators are not qualified by reason of their

scientific training and experience to conduct the investigation described in the IND application

• Investigator Brochure is misleading, erroneous, or incomplete • IND application does not contain sufficient information to

assess the risks to subjects • Inadequately described product preparation or formulation• IND application is for the treatment of a life-threatening or

serious disease affecting both genders and only one gender is included in the proposed trial and there are no plans to include both genders in subsequent trials

Phase 2 and 3 studies• Any of the above, OR • The protocol is deficient in design to meet its stated objectives

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When your IND Could be Release from Clinical Hold

• FDA sends a letter stating the reasons for hold and how to address them

• IND sponsor submits a written response to be reviewed within 30 days • If the response is adequate, the sponsor is

released from hold and the IND application is in effect • FDA sends a letter stating the study may proceed.

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Cell and Gene Therapies: Unique IssuesComplexity of products• May impose practical limits on dose produced. on the

concentration or volume that can be delivered• Might restrict the range of doses that are feasiblePreliminary assessments of product activity, short-term responses or longer-term outcomes---e.g.,• Gene expression• Cell engraftment• Changes in immune function• Physiologic responses• Prospective biomarkers

• volume that can be delivered• Might restrict the range of doses that are feasible

62

Cell and Gene Therapies: (cont)Choice of Study Population

• FDA looks at overall risk-benefit for the study population

FDA looks at overall risk-benefit for the study population • Healthy normal subjects are almost never included in trials for cellular and

gene therapy products- Products might have long-term risks or permanent adverse effectsPatients with advanced disease and limited options• Might be preferred population, if they make the risks acceptable in spite of

uncertain benefit• Might be more vulnerable to complications of adverse reactions, which might

increase the risks• Confounding adverse events due to underlying disease could make safety

data difficult to interpret• Advanced disease state may present irreversible pathology, which may not

respond to the experimental therapy

never included in trials for cellular and gene therapy proP d t i ht h l t

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Cell and Gene Therapies: (cont) Treatment Plan

• Most first-in-human trials of cellular and gene therapies include staggered administration to limit overall risk

• Staggered administration– The interval is intended to be long enough to monitor for acute and

subacute adverse events• Cohort size can vary depending on the amount of risk that is

acceptable for the indication• Smaller cohorts might be adequate for a product intended to improve

survival• Larger cohorts may be useful to provide assurance about safety before

escalating the dose of a product expected to provide only a modest benefit

• ene therapies include staggered administration to limit overall risk • Staggered administration

– There is a specified follow-up interval between administration to the first subject and administration to the second subject– The interval is intended to be long enough to monitor for acute and subacute adverse events

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How to avoid problems

• Don’t ignore Pre-IND Input from FDA!• Create reviewer-friendly IND submission• Include copy of the protocol, including details of safety monitoring plan• Provide background information and scientific rationale for your study• Don’t forget to include previous human experience (letter of cross

reference)• Provide your rationale for the dose selection• Endpoints (primary and secondary)• Individual and study stopping rules• Informed Consent and Informal assent forms• Be available for any discussion during the first 30 days!

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Opportunities for Interaction --Clinical Development

65

IND submission

INTERACTPre-INDMeeting

End of Ph 1 Meeting

End of Ph 2 Meeting

Pre-BLAMeeting

PDUFA VMeetings

Safety Meetings

Clinical TrialsPreclinical Marketing Application Post-marketing

BLAPhase 3Phase 2Phase 1PreclinicalDevelopment Post marketing

66

CBER InitiativesFacilitating additional Interactions with FDA INTERACT (Initial Targeted Engagement for Regulatory Advice on CBER

products) INTERACT Meetings Program was created for potential sponsors to engage with CBER

staff and obtain advice on a specific topic or issue that is critical to early product development

Email: interact-cber@fda.hhs.gov RMAT (Regenerative Medicine Advanced Therapy) Sponsors of cell and gene therapies are eligible to obtain an RMAT designation if their

product is intended to treat serious or life-threatening diseases and there is preliminary clinical evidence that the product can address unmet medical needs.

All benefits of Breakthrough designation: meeting with FDA throughout development, rolling review, intensive guidance on efficient product development beginning as early as Phase 1 and more.

www.fda.gov

67

Guidances

• Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products (June 2015) http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM359073.pdf

Three draft Gene Therapy Guidance documents in 2018:• Treatment of Hemophilia• Treatment of Retinal Disorders• Treatment of Rare Diseases

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Contact Information Rachel Witten, M.D.

Email: rachel.witten@fda.hhs.gov

Regulatory Questions:

OTAT Main Line – 240 402 8190Email: OTATRPMS@fda.hhs.gov and

Lori.Tull@fda.hhs.gov

OTAT Learn Webinar Series:

http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm

CBER website: www.fda.gov/BiologicsBloodVaccines/default.htm

Phone: 1-800-835-4709 or 240-402-8010

Consumer Affairs Branch: ocod@fda.hhs.gov

Manufacturers Assistance and Technical Training Branch: industry.biologics@fda.gov Follow us on Twitter: https://www.twitter.com/fdacber

FDA Headquarters